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HORMONES AND SIGNALING

Dual alterations in casein kinase I- and GSK-3 modulate -catenin stability in hyperproliferating colonic epithelia

¹Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Texas Medical Branch, Galveston; and ²Department of Integrative Biology, University of Texas Health Science Center, Houston, Texas

Submitted 27 July 2006 ; accepted in final form 17 October 2006

Casein kinase I (CKI)- and GSK-3 phosphorylate -catenin at Ser⁴⁵ (-cat⁴⁵) and Thr⁴¹/Ser^37,33 (-cat^33,37,41) residues, thereby facilitating its ubiquitination and proteasomal degradation. We used a Citrobacter rodentium-induced transmissible murine colonic hyperplasia (TMCH) model to determine Ser/Thr phosphorylation and biological function of -catenin during crypt hyperproliferation. TMCH was associated with 3-fold and 3.3-fold increases in CKI- cellular abundance and 2-fold and 1.8-fold increase in its activity at 6 and 12 days after infection, respectively. -Catenin coimmunoprecipitated with both cellular and nuclear CKI- and cellular axin at these time points. Cellular -catenin was constitutively phosphorylated at Ser⁴⁵ and underwent subcellular redistribution to cytoskeletal and nuclear fractions at days 6 and 12 of TMCH, respectively. -cat^33,37,41, however, exhibited only subtle changes in either phosphorylation status or subcellular distribution even after blocking proteasomal degradation in vivo. Interestingly, GSK-3 underwent increased phosphorylation at Ser⁹, leading to 40% and 70% decreases in its activity at these time points, respectively. Coimmunoprecipitation studies exhibited strong association of GSK-3 with PKC- at either time point. Cellular -cat⁴⁵ stabilized and, along with unphosphorylated -catenin, underwent nuclear translocation, associated with nuclear accumulated Tcf-4 and cAMP response element binding protein binding protein, and was significantly acetylated, leading to increases in DNA binding. Priming of -catenin at Ser⁴⁵ exists in vivo. However, -cat⁴⁵ does not necessarily enter the degradation pathway. Impairment in linking -cat⁴⁵ to subsequent GSK-3-mediated phosphorylation and degradation may account for increased steady-state levels of both unphosphorylated as well as Ser⁴⁵-phosphorylated -catenin, which may be causally linked to increases in cell census during TMCH.

colon; hyperproliferation